This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Meng-Que Xu, Hai-Long Cao, Wei-Qiang Wang, Shan Wang, Xiao-Cang Cao, Fang Yan, Bang-Mao Wang, Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300052, China
Fang Yan, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232-0696, United States
ORCID number: $[AuthorORCIDs]
Author contributions: Xu MQ, Cao HL, Wang S, Cao XC and Wang BM designed the review; Xu MQ and Cao HL analyzed the data; Xu MQ, Cao HL, Wang S and Cao XC wrote the paper; Xu MQ, Cao HL, Yan F and Wang WQ revised the manuscript.
Supported by Grants (No. 81470796 to Yan F, No. 81070283 to Wang BM and No. 81300272 to Cao HL) from the National Natural Science Foundation of China, a grant (No. 20121202110018 to Wang BM) from the Research Fund for the Doctoral Program of Higher Education of China, and a grant (No. 13JCQNJC10600 to Cao HL) from Tianjin Research Program of Application Foundation and Advanced Technology of China
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hai-Long Cao, MD, Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, 154 Anshan Rd, Heping District, Tianjin 300052, China. firstname.lastname@example.org
Telephone: +86-22-60362608 Fax: +86-22-27813550
Received: July 28, 2014 Peer-review started: July 29, 2014 First decision: August 15, 2014 Revised: August 30, 2014 Accepted: October 15, 2014 Article in press: October 15, 2014 Published online: January 7, 2015
Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson’s disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis.
Core tip: Fecal microbiota transplantation (FMT) achieved a successful cure rate in recurrent Clostridium difficile infection. Although there is a deficiency of randomized controlled trials, the present review reveals that FMT could be a promising rescue therapy in extra-intestinal disorders associated with gut microbiota, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors.
Citation: Xu MQ, Cao HL, Wang WQ, Wang S, Cao XC, Yan F, Wang BM. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol 2015; 21(1): 102-111
The human intestinal tract is home to up to 1014 microbes, outnumbering human cells within our bodies by tenfold[1,2]. The number and diversity of bacteria differ according to the different anatomical areas, ranging from the proximal to the distal gastrointestinal tract, with the colon harboring most of the intestinal microbiota. Such an environment developed by host-bacteria associations is termed as being mutualistic. Four predominant bacterial phyla are identified in the human intestine: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria.
Rather than simply occupying space in our bodies, the intestinal microbiota is essential to nutrient metabolism, opportunistic pathogens defense, immune system development, and intestinal-barrier function regulation[3,6,7]. The specific balance of intestinal microbial diversity differs by individual according to variations (such as sanitation, social behaviors, and genetics)[8,9]. The beneficial balance of the intestinal microbial ecosystem can be disrupted by a series of factors, which includes antimicrobial drugs, vaccination, and dietary shifts. Previous studies have suggested that intestinal microbiota alterations have been implicated in many gastrointestinal diseases and even systemic illnesses, such as metabolic diseases[10,11], neuropsychiatric conditions, autoimmune diseases, allergic disorders, and tumors.
Fecal microbiota transplantation (FMT) is a technique in which intestinal microbiota are transferred from a healthy donor to the patient, with the goal being to introduce or restore a stable microbial community in the gut. The first use of feces in such a manner was described, according to the Handbook of Emergency Medicine, approximately 1700 years ago by a Chinese medical scientist named Ge Hong. It was first published in the English language by Eiseman et al in 1958, when he reported a prompt response in patients with antibiotic-associated diarrhea treated with fecal enemas. Nevertheless, this practice was not well recognized until 1978, when investigators recognized Clostridium difficile infection (CDI) was the etiology of antibiotic-associated pseudomembranous colitis[18,19]. In the past few decades, the use of FMT for managing the increasing burdens of CDI has demonstrated it to be an effective therapeutic strategy for CDI[20-23]. In 2012, Borody et al reported that more than 1200 cases have been treated in several centers. A total of 583 CDI patients treated with FMT produced a cumulative cure rate of more than 90% in 36 publications. In addition, standardized frozen donor fecal bacterial preparations used in the treatment of recurrent CDI showed equal cure rates to fresh fecal samples. 2013 guidelines for CDI have recommended that FMT should be considered if there is a third recurrence after a pulsed vancomycin regimen.
Although there are still many areas of uncertainty concerning this emerging technology, including transmission of infectious organisms, long-term sequelae, and even cost-effective evaluation, the United States Food and Drugs Administration have recently paid critical attention to FMT protocol in clinical applications. Borody et al regarded the flora in feces as a special organ, and therefore considered the technique of FMT as a particular type of organ transplantation, regardless of the issue of immunological rejection. FMT has hence emerged as an important therapeutic modality in the manipulation of altered intestinal microbiota, with the indications of FMT possibly being expanded to even extra-intestinal conditions.
RATIONALE FOR FMT
The exact mechanisms by which intestinal dysbiosis becomes involved in disease development are not completely elucidated. Alteration of metabolic activities induced by perturbed intestinal bacterial species leads to weakened defense of the gastrointestinal mucosa, which in turn leads to increasing intestinal permeability and toxic substances being absorbed into the systemic circulation. Prior work has observed disruption of the intestinal microbiota being evident at the phylum level, with marked depletion in levels of probiotics and a relative increase in the numbers of pathogens leading to complications in intestinal conditions. The alteration of microbial communities in both inflammatory bowel disease (IBD) and CDI patients was characterized by a reduction in two phyla of bacteria, Firmicutes and Bacteroidetes, which are prominent in healthy controls[28,29]. Moreover, an increase in Proteobacteria such as Enterobacteriaceae is also found in individuals with IBD. Bacteroides fragilis, the prominent human gut commensal, can prevent and cure inflammatory disease via the effect of its symbiosis factor (polysaccharide A, an immunomodulatory bacterial molecule) on the activation of the Toll-like receptor 2 pathway, inducing regulatory T cells and interleukin-10 production. Dextran sodium sulfate-induced colitis in a mouse model demonstrated that spore-forming Firmicutes in clostridial clusters IV and XIVa reduced intestinal inflammation through regulatory T cells induction.
These studies highlight the role of microbiota-target therapy for reinstalling the depleted bacterial species associated with the disease. Probiotics somehow alter the metabolism of the indigenous gut flora, although the effect is largely restricted to limited bacterial species, and have a transient inhabitation effect on the intestine. Nevertheless, the satisfactory outcome of treatment with FMT suggests that feces contain a superior combination of intestinal bacterial strains and is more favorable for repairing disrupted native microbiota by introducing a complete, stable community of intestinal micro-organisms. Feces also harbors additional substances (proteins, bile acids, and vitamins) which might contribute to the recovery of gut function.
This scenario has in fact been documented in a recent study of FMT in recurrent CDI trying to elucidate the mechanism of action of fecal infusion. The authors assessed the characteristics of fecal microbiota before, after, and during follow-up of FMT and found the intestinal microbiota changed persistently over time, from a less-diverse disease state (pre-FMT) to a more diverse ecosystem virtually resembling that of fecal donors (post-FMT). Such dynamic monitoring of the intestinal microbiota helps us to identify the key groups representing the ecosystem, as well as further illustrating that normalization of the bowel function was accompanied by the engraftment of intestinal micro-organisms from a healthy donor. Currently, there is significant interest in the area of FMT in IBD, especially with the evidence of an impressive curable effect in some ulcerative colitis (UC) patients[35,36]. A study was conducted to determine microbiota composition after FMT in 5 patients with UC by monitoring their fecal bacterial communities at multiple time points. The results showed that one patient had a positive response to FMT, which was characterized by the augmentation of donor-derived microbiota, including Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. According to Borody et al Crohn’s disease (CD) is less responsive to FMT when compared with UC. Nonetheless, recent case reports have shown the promising future of FMT as a rescue therapy for CD[39-41]. Data on the application of FMT in irritable bowel syndrome (IBS) is limited to a case series of 55 patients which showed that 36% of patients were regarded as curable while 16% had symptoms reduced[42,43]. To better understand the role of the intestinal microbiota in the etiology and effective treatment of IBD and IBS, future controlled trials are necessary.
For this reason, the core mechanism for the efficacy of FMT is likely to be the establishment of intestinal bacterial strains and antimicrobial components (adhesin, immunomodulatory molecules, bacteriocin, etc.) produced by these associated strains. Adhesin molecules can compete for sites with pathogens, leading to them being prevented from colonizing in the intestine and rehabilitating the intestinal microbiota.
SAFETY OF FMT
When FMT entered the medical community, it became a relatively hot therapeutic strategy, bringing with it both promise and controversy. According to published articles, transient adverse responses after FMT have been reported, including mild fever, abdominal pain, diarrhea, exhaust, flatulence, and fatigue. However, these adverse effects are self-limiting. De Leon et al reported a UC patient quiescent for more than 20 years who developed a flare of UC after FMT. This case gives us cautionary information concerning FMT being used to treat CDI with UC. Moreover, a recent paper reported a UC patient who had a cytomegalovirus infection after performing home FMT without donor screening. As extracts of feces are mediators between the donor and recipient, FMT has the potential for transmitting occult infections even when strict donor screening is performed.
FMT FOR EXTRA-INTESTINAL DISORDERS
It seems to be serendipitous that the CDI epidemic facilitated the application of FMT to many other diseases (Table 1). The pathogenesis of gut microbiota in extra-intestinal diseases was inspired by massive studies in germ-free (GF) animals. Complete construction of the hypothalamic-pituitary-adrenal axis requires the participation of gut microbiota. GF mice exhibit a dysregulation of the axis, thereby resulting in altered brain-derived hormones (e.g., norepinephrine and tryptophan) and increased caloric intake. Aside from the crucial role of intestinal microbiota in central nervous system activity, another concept is emerging which was termed as “bidirectional brain-gut-microbiota axis”[46-48]. The destruction of the axis leads to altered behaviors and various neurologic conditions[49,50]. Identically, ample human studies have provided evidence for the critical role of the gut microbiota in extra-intestinal disorders.
Table 1 Summary of extra-intestinal disorders associated with gut microbiota.
1Fecal microbiota transplantation used in these studies. RCT: Randomized controlled trial; ITP: Idiopathic thrombocytopenic purpura; SS: Sjögren's syndrome; SLE: Systemic lupus erythematosus.
There is compelling evidence that the intestinal microbiota is closely linked to a series of metabolic conditions. Obesity, diabetes mellitus, and metabolic syndrome are epidemic in modern society. There have been extensive investigations concerning microbiota reaction acting as a pivotal role in the pathogenesis of these endocrine diseases in animal models[51,52]. Changes in gut microbiota composition have also been reported in obese humans[53-55], with a shift in the ratio of Firmicutes and Bacteroidetes. Meanwhile, increased levels of bacteria and their metabolic products were found in the plasma of obese individuals, with one likely mechanism thought to be increased intestinal permeability[57,58]. Recent studies have shown that short chain fatty acid (including butyrate) producing Clostridiales strains (Roseburia and Faecalibacterium prausnitzii) were found to be decreased in patients with type 2 diabetes mellitus, but non-butyrate producing Clostridiales and pathogens such as Clostridium clostridioforme were increased[59,60]. Vrieze et al conducted a double blind, randomized controlled trial of FMT in 18 male patients with metabolic syndrome. Half of them received fecal microbiota infusion from lean male donors (allogenic group), while the other half received auto-fecal transplants (control group). The results showed that both insulin sensitivity and levels of butyrate-producing intestinal microbiota (Roseburia intestinalis and Eubacterium hallii) were markedly increased after a six-week infusion of microbiota from lean donors, while no significant changes were found in the control group. In the group following allogenic gut microbiota transfer, the median rate of glucose disappearance increased from 26.2 to 45.3 μmol/kg per minute, while the median endogenous glucose production increased from 51.5% to 61.6%. Hence, it can be speculated that FMT could be developed as a potential therapeutic strategy for increasing insulin sensitivity in humans.
Leaky gut or loss of intestinal integrity may facilitate the development of cardiometabolic disorders due to alterations in composition and diversity of gut microbiota. A close association of microbial translocation with the risk of cardiovascular disease (CVD) have recently been established[62,63], with probiotic bacteria having raised plasma unconjugated bile acid concentrations through modulation of the enterohepatic circulation. It also concomitantly reduced the lipid uptake from the intestine and the plasma cholesterol level, an indirect risk marker of CVD, by means of regulation of a series of signaling molecules, such as Farnesoid X receptor-α and G-protein-coupled receptors. One study illustrated the negative impact of trimethylamine-N-oxide, an atherogenic compound produced by intestinal flora from choline and betaine[65,66], on the morbidity and mortality of cardiovascular events. A variety of data have clearly demonstrated that the intestinal microbiota act as an independent risk factor for CVD, as well as representing a promising therapeutic target for this disease.
An increasing body of published evidence has recently been generated that demonstrates that demonstrates the gut microbiota act as an epigenetic factor driving the progression of non-alcoholic fatty liver disease (NAFLD)[68-70], a metabolic syndrome that manifests in the liver. Intestinal dysbiosis promotes hepatic injury and inflammation through either a breakdown of the intestinal barrier or translocation of microbial products. Abundant studies using GF mice models have illustrated that these special organisms are resistant to steatosis and diet-induced obesity. Le Roy et al performed an animal study to clarify the role of gut microbiota in the development of NAFLD. They divided the conventional mice into two groups (responder and non-responder) according to their response to a high-fat diet (HFD), and found that GF mice receiving FMT from different donors (responder and non-responder) developed comparable results on the HFD. The GF group that received microbiota from the responder group developed steatosis and harbored a larger number of Barnesiella and Roseburia, whereas Allobaculum was higher in the other group. Further evidence has proved that intestinal permeability increased and endotoxemia developed in NAFLD patients. This indicates that microbiota-targeting therapy might be useful in treating NAFLD and obesity.
A high incidence rate of constipation is found in Parkinson’s disease (PD) patients. Constipation can precede the onset of motor symptoms by more than 10 years, indicating the disease may start in the intestine. A man suffered from PD and characterized with the motor symptoms of marked pill-rolling hand tremors, micrographia, cogwheel rigidity, and chronic constipation. He received antibiotic therapy (vancomycin, colchicine, and metronidazole) for his constipation and reported an improvement in gastrointestinal symptoms. After consistent therapy for 10 mo, his neurologic symptoms disappeared. This case cured by antibiotics suggests that the gut microbiota are involved in the pathogenesis of PD. The results of symptomatic improvement in PD patients by FMT indicate a new way of thinking for clinicians.
Both animal and clinical studies have shown that the pathogenesis of multiple sclerosis (MS) is associated with the intestinal microbiota[76,77]. Three patients with MS who underwent FMT for constipation achieved normal defecation and virtually complete normalization of neurological symptoms, thereby improving their quality of life. Borody et al reported a case of a young female patient with myoclonic dystonia and chronic diarrhea. The symptoms had co-developed since she was 6 years old and progressed in severity to a plateau. FMT resulted in a rapid improvement in diarrhea symptoms, a 90% improvement in her myoclonus dystonia symptoms, and, as a consequence of restoring her fine motor function, improving her ability to perform tasks that require dexterity, such as holding cups and fastening buttons.
Autism is another condition in which intestinal microbiota is implicated. The onset of autism is often accompanied by intestinal dysfunction[79-81]. The first description of an association between autism and gastrointestinal syndrome began in 1971, with a report that 6 out of 15 autism patients had changed fecal character and defecation frequency. Finegold et al performed an intestinal flora study in regressive autism. It is compelling to observe that there were higher counts of Clostridium and Ruminococcus spp. in the stools of autistic children when compared to those in the control group. Nine clostridial species were found in autistic children, while only three were found in healthy children. The authors further observed histologic changes in the gastric and duodenal specimens. Moreover, significant higher numbers of non-spore- forming anaerobes and microaerophilic bacteria were found in autistic children. Based on the hypothesis that autism involves intestinal microbiota, Song et al characterized Clostridia from the feces of autistic and control children. The data indicate that counts of Clostridium bolteae and clusters I and XI in autistic group are largely greater than those in control children. There was evidence of autistic symptom remission in two children after FMT. Parallel results were also presented in five children who received daily cultured Bacteroidetes and Clostridia for several weeks.
Alterations in the intestinal flora have also been observed in patients with chronic fatigue syndrome (CFS). The proportion of gram-negative Escherichia coli was reduced in CFS patients versus that in healthy controls (49% vs 92.3%). More recent research examined a larger cohort of 60 CFS patients with gastrointestinal symptoms who had underwent FMT. The results showed that 42/60 (70%) patients responded to treatment and 7/12 (58%) retained complete resolution of symptoms during a 15-20 year follow-up period. These results, suggest that FMT may play a role in the treatment of CFS.
The incidence of autoimmune diseases has dramatically increased, but the causes of these conditions remain poorly understood. Idiopathic thrombocytopenic purpura (ITP) is caused by the production of autoantibodies against platelet surface antigens. In a patient with ITP who was treated with FMT for UC, prolonged reversal of ITP was reported and the normalization of platelet levels was achieved.
The onset of rheumatoid arthritis (RA) is multifactorial and requires both genetic and environmental influential factors, with the commensal intestinal microbiota playing a major role[13,86,87]. Alterations in the intestinal microbiome can have an extended effect on RA through mucosal immune activation. Previous reports have implicated Prevotella copri in the pathogenesis of RA. A recent study used the interleukin-1 receptor antagonist deficient (IL-1Ra-/-) mouse model, which can spontaneously develop T cell-driven IL-17-dependent autoimmune arthritis. It was shown that IL-1Ra-/- mice had increased Th17 and a reduced proportion of Th1 in small intestinal lamina propria compared with wild-type mice. GF IL-1Ra-/- mice had lower levels of both Th1 and Th17. Interestingly, IL-1Ra-/- mice previously treated by antibiotics was recolonized by segmented filamentous bacteria, a prominent Th17 inducer, leading to full-fledged arthritis. Moreover, elimination of intestinal Gram-negative commensals suppressed the progression of arthritis. Understanding the role of the intestinal microbiota in the onset of RA may provide significant attention to FMT with regards to management of the disease; the potential is therefore worthy of consideration.
In both Sjögren’s syndrome (SS) and systemic lupus erythematosus (SLE), Sjögren’s syndrome antigen A/Ro60 is one of the main autoantigens. Ro60 reactive autoantibodies are associated with manifestation severity in SS and with photosensitivity in SLE. Escherichia coli expresses von Willebrand factor type A domain protein, which can activate Ro60-reactive T cells. Therefore, immune responses to the gut microbiota may play a pivotal role in the initiation of autoimmunity in SLE and SS. This sheds a light on a novel therapeutic strategy for the diseases.
Hashimoto’s thyroiditis (HT) is a thyroid autoimmune disorder, and a series of studies have been implemented to explore the link between gut micro-organisms and HT[92-95]. Although no data on gut microbiota composition are available in HT, increased intestinal permeability was detected in patients with HT. The onset of HT is associated with Yersinia enterocolitica, though conflicting data has also been presented[92,95]. Further work is required to test the hypothesis that the gut microbiota is an epigenetic factor for triggering HT, and thereby determine whether FMT is favorable for managing the illness.
The prevalence of allergic diseases has been increasing in modern society over the past 50 years. To date, there are two hypotheses for the allergy pandemic: the hygiene hypothesis and the microbiota hypothesis. The latter hypothesis suggests that the disruption of intestinal microbiota drives the emergence of allergy. A wealth of studies regarding the relationship between allergic diseases and microbiota has been conducted in both humans and mice. In the model of allergic airway inflammation induced by ovalbumin/alum, GF mice develop more severe allergic disease than conventional mice[100,101]. Moreover, accumulating evidence has suggested early-life antibiotic exposure is involved in the development of atopy, such as allergic asthma and food allergies, with an altered composition of intestinal microbiota possibly being involved[102,103]. Though probiotic strategies have shown some promise in animal models in preventing asthma development[104,105], it has had little success in humans[106,107]. The use of FMT seems promising in restoring immune homeostasis by transferring a complex community of bacteria which is more stable and harbors a greater ability to colonize.
POTENTIAL THERAPEUTIC ROLE IN EXTRA-INTESTINAL TUMORS
A strong association has now been illustrated between the intestinal microbiota (e.g., Streptococcus bovis, Enterococcus spp, enterotoxigenic Bacteroides fragilis, pathogenic Escherichia coli, and Fusobacterium nucleatum) and colorectal cancer[108-110]. Recently, incremental data has suggested that the gut flora (namely Streptococcus bovis and Helicobacter hepaticus) might be involved in extra-intestinal tumors. Gold et al reviewed 8 extraintestinal malignancies [3 pancreatic adenocarcinomas, 1 lung cancer, 1 ovarian cancer, 1 endometrial cancer, 2 non-solid-organ malignancies (1 chronic myelogenous leukemia with blast crisis and 1 chronic lymphocytic leukemia with end-stage liver disease)] in 45 cases with Streptococcus bovis bacteremia in a retrospective study, which suggested that extraintestinal malignancy might be warranted in patients with Streptococcus bovis. In addition, prior work has shown the gut microbiota is also involved in mammary tumors[111,112]. The authors infected recombination-activating gene 2-deficient multiple intestinal neoplasia (ApcMin/+) mice with Helicobacter hepaticus and found the gut flora modulated the carcinogenesis of both mammary carcinoma and intestinal adenocarcinoma in females by triggering inflammatory responses. On a similar note, Rao et al emphasized the question as to whether the gut bacteria should be examined in terms of prevention and treatment for mammary cancer.
In addition, Fox et al used a mouse model to examine the hypothesis that specific intestinal bacteria were associated with hepatocarcinogenesis. The progress of hepatocellular carcinoma induced by aflatoxin and hepatitis C transgene was promoted by Helicobacter hepaticus colonization in the intestine through activation of the nuclear factor-κB pathway, which was associated with immunity in the intestine and liver. Surprisingly, neither hepatitis nor bacterial translocation to the liver was essential during this course. These results lead us to think of intestinal bacteria as an attractive therapeutic target.
More recently, Yamamoto et al investigated the relationship between the gut microbiota and lymphoma. Using an Atm-/- mouse model (mice with ataxia-telangiectasia, which can eventually developed into lymphoma), the authors compared the incidence of lymphoma in isogenic mice reared in 2 distinct housing conditions, and found that the gut microbiota acted as a potential contributor to lymphoma onset. Meanwhile, Lactobacillus johnsonii was identified to be abundant in more cancer-resistant mice and was further tested for its ability to confer reduced systemic inflammation and genotoxicity when re-established by oral transfer. Given that gut microbiota impact lymphoma incidence and latency, FMT holds promise for reducing lymphoma risk in susceptible individuals.
FMT is proven to be a well-established procedure and the most effective therapy for recurrent CDI to date. Case studies suggest that FMT also has potential clinical applications in treating a wide spectrum of other conditions associated with intestinal dysbiosis. However, additional high quality data are urgently needed to further establish the efficacy of FMT. It is expected that the standardization of FMT will be established in the coming years and its indications expanded. For this reason, besides conventional approaches, FMT is promising as an alternative therapy for many extra-intestinal disorders associated with gut microbiota.
P- Reviewer: Blanco LP, Krishnan T S- Editor: Gou SX L- Editor: Rutherford A E- Editor: Wang CH
Savage DC. Microbial ecology of the gastrointestinal tract.Annu Rev Microbiol. 1977;31:107-133.
Salonen A, Palva A, de Vos WM. Microbial functionality in the human intestinal tract.Front Biosci (Landmark Ed). 2009;14:3074-3084.
Khanna S, Tosh PK. A clinician’s primer on the role of the microbiome in human health and disease.Mayo Clin Proc. 2014;89:107-114.
Zoetendal EG, Vaughan EE, de Vos WM. A microbial world within us.Mol Microbiol. 2006;59:1639-1650.
Borody TJ, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues.Gastroenterol Clin North Am. 2012;41:781-803.
Bäckhed F, Fraser CM, Ringel Y, Sanders ME, Sartor RB, Sherman PM, Versalovic J, Young V, Finlay BB. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications.Cell Host Microbe. 2012;12:611-622.
Tappenden KA, Deutsch AS. The physiological relevance of the intestinal microbiota--contributions to human health.J Am Coll Nutr. 2007;26:679S-683S.
Flint HJ. The impact of nutrition on the human microbiome.Nutr Rev. 2012;70 Suppl 1:S10-S13.
Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP. Human gut microbiome viewed across age and geography.Nature. 2012;486:222-227.
Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction.J Clin Invest. 2011;121:2126-2132.
Zhao L. The gut microbiota and obesity: from correlation to causality.Nat Rev Microbiol. 2013;11:639-647.
Hornig M. The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness.Curr Opin Rheumatol. 2013;25:488-795.
Luckey D, Gomez A, Murray J, White B, Taneja V. Bugs & amp; us: the role of the gut in autoimmunity.Indian J Med Res. 2013;138:732-743.
Russell SL, Finlay BB. The impact of gut microbes in allergic diseases.Curr Opin Gastroenterol. 2012;28:563-569.
Gold JS, Bayar S, Salem RR. Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy.Arch Surg. 2004;139:760-765.
Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation?Am J Gastroenterol. 2012;107:1755; author reply p.1755-p.1756.
Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis.Surgery. 1958;44:854-859.
Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever.N Engl J Med. 2008;359:1932-1940.
van Nood E, Speelman P, Nieuwdorp M, Keller J. Fecal microbiota transplantation: facts and controversies.Curr Opin Gastroenterol. 2014;30:34-39.
Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection.Clin Infect Dis. 2011;53:994-1002.
De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection.Clin Gastroenterol Hepatol. 2013;11:1036-1038.
Zanella Terrier MC, Simonet ML, Bichard P, Frossard JL. Recurrent Clostridium difficile infections: the importance of the intestinal microbiota.World J Gastroenterol. 2014;20:7416-7423.
Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications.Nat Rev Gastroenterol Hepatol. 2012;9:88-96.
Dodin M, Katz DE. Faecal microbiota transplantation for Clostridium difficile infection.Int J Clin Pract. 2014;68:363-368.
Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection.Am J Gastroenterol. 2012;107:761-767.
Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.Am J Gastroenterol. 2013;108:478-498; quiz 499.
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease.Nat Rev Immunol. 2009;9:313-323.
Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea.J Clin Gastroenterol. 2010;44:354-360.
Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.Science. 2011;332:974-977.
Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y. Induction of colonic regulatory T cells by indigenous Clostridium species.Science. 2011;331:337-341.
Fuentes S, van Nood E, Tims S, Heikamp-de Jong I, ter Braak CJ, Keller JJ, Zoetendal EG, de Vos WM. Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection.ISME J. 2014;8:1621-1633.
Allegretti JR, Hamilton MJ. Restoring the gut microbiome for the treatment of inflammatory bowel diseases.World J Gastroenterol. 2014;20:3468-3474.
Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease.Aliment Pharmacol Ther. 2012;36:503-516.
Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H, Cloney D, Kugathasan S. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis.J Pediatr Gastroenterol Nutr. 2013;56:597-601.
Angelberger S, Reinisch W, Makristathis A, Lichtenberger C, Dejaco C, Papay P, Novacek G, Trauner M, Loy A, Berry D. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation.Am J Gastroenterol. 2013;108:1620-1630.
Borody TJ, Finlayson S, Paramsothy S. Is Crohn’s disease ready for fecal microbiota transplantation?J Clin Gastroenterol. 2014;48:582-583.
Zhang FM, Wang HG, Wang M, Cui BT, Fan ZN, Ji GZ. Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn’s disease.World J Gastroenterol. 2013;19:7213-7216.
Kao D, Hotte N, Gillevet P, Madsen K. Fecal microbiota transplantation inducing remission in Crohn’s colitis and the associated changes in fecal microbial profile.J Clin Gastroenterol. 2014;48:625-628.
Gordon H, Harbord M. A patient with severe Crohn’s colitis responds to Faecal Microbiota Transplantation.J Crohns Colitis. 2014;8:256-257.
Borody TJ, Paramsothy S, Agrawal G. Fecal microbiota transplantation: indications, methods, evidence, and future directions.Curr Gastroenterol Rep. 2013;15:337.
Borody TJ, George L, Andrews P, Brandl S, Noonan S, Cole P, Hyland L, Morgan A, Maysey J, Moore-Jones D. Bowel-flora alteration: a potential cure for inflammatory bowel disease and irritable bowel syndrome?Med J Aust. 1989;150:604.
Hohmann EL, Ananthakrishnan AN, Deshpande V. Case Records of the Massachusetts General Hospital. Case 25-2014. A 37-year-old man with ulcerative colitis and bloody diarrhea.N Engl J Med. 2014;371:668-675.
Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease.Physiol Rev. 2010;90:859-904.
Pennisi E. Mysteries of development. How do microbes shape animal development?Science. 2013;340:1159-1160.
Wang Y, Kasper LH. The role of microbiome in central nervous system disorders.Brain Behav Immun. 2014;38:1-12.
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease.Gastroenterology. 2009;136:2003-2014.
Ueki A, Otsuka M. Life style risks of Parkinson’s disease: association between decreased water intake and constipation.J Neurol. 2004;251 Suppl 7:vII18-vII23.
Murphy EF, Cotter PD, Healy S, Marques TM, O’Sullivan O, Fouhy F, Clarke SF, O’Toole PW, Quigley EM, Stanton C. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models.Gut. 2010;59:1635-1642.
Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, Pan C, Civelek M, Rau CD, Bennett BJ. Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.Cell Metab. 2013;17:141-152.
Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease.Proc Natl Acad Sci USA. 2012;109:594-599.
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP. A core gut microbiome in obese and lean twins.Nature. 2009;457:480-484.
Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA, Donus C, Hardt PD. Microbiota and SCFA in lean and overweight healthy subjects.Obesity (Silver Spring). 2010;18:190-195.
Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients.PLoS One. 2009;4:e7125.
Teixeira TF, Collado MC, Ferreira CL, Bressan J, Peluzio Mdo C. Potential mechanisms for the emerging link between obesity and increased intestinal permeability.Nutr Res. 2012;32:637-647.
Kootte RS, Vrieze A, Holleman F, Dallinga-Thie GM, Zoetendal EG, de Vos WM, Groen AK, Hoekstra JB, Stroes ES, Nieuwdorp M. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus.Diabetes Obes Metab. 2012;14:112-120.
Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D. A metagenome-wide association study of gut microbiota in type 2 diabetes.Nature. 2012;490:55-60.
Udayappan SD, Hartstra AV, Dallinga-Thie GM, Nieuwdorp M. Intestinal microbiota and faecal transplantation as treatment modality for insulin resistance and type 2 diabetes mellitus.Clin Exp Immunol. 2014;177:24-29.
Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.Gastroenterology. 2012;143:913-916.e7.
Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011;472:57-63.
Trøseid M, Manner IW, Pedersen KK, Haissman JM, Kvale D, Nielsen SD. Microbial translocation and cardiometabolic risk factors in HIV infection.AIDS Res Hum Retroviruses. 2014;30:514-522.
Tuohy KM, Fava F, Viola R. ‘The way to a man’s heart is through his gut microbiota’--dietary pro- and prebiotics for the management of cardiovascular risk.Proc Nutr Soc. 2014;73:172-185.
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.N Engl J Med. 2013;368:1575-1584.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.Nat Med. 2013;19:576-585.
Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, Koeth RA, Levison BS, Fan Y, Wu Y, Hazen SL. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide.Eur Heart J. 2014;35:904-910.
Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice.Gut. 2013;62:1787-1794.
Delzenne NM, Cani PD. Interaction between obesity and the gut microbiota: relevance in nutrition.Annu Rev Nutr. 2011;31:15-31.
Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease.Nat Rev Gastroenterol Hepatol. 2010;7:691-701.
Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease.Curr Pharm Des. 2010;16:1941-1951.
Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014;146:1513-1524.
Rabot S, Membrez M, Bruneau A, Gérard P, Harach T, Moser M, Raymond F, Mansourian R, Chou CJ. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism.FASEB J. 2010;24:4948-4959.
Ananthaswamy A. Faecal transplant eases symptoms of Parkinson’s disease.New Sci. 2011;209:8-9.
Guseo A. [The Parkinson puzzle].Orv Hetil. 2012;153:2060-2069.
Borody TJ, Leis SM, Campbell J, Torres M, Nowak A. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS) [abstract].Am J Gastroenterol. 2011;106:S352.
Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.Cell. 2005;122:107-118.
Borody TJ, Rosen DM, Torres M, Campbell J, Nowak A. Myoclonus-dystonia (M-D) mediated by GI microbiota diarrhoea treatment improves M-D symptoms.Am J Gastroenterol. 2011;106:S352.
Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM. Gastrointestinal microflora studies in late-onset autism.Clin Infect Dis. 2002;35:S6-S16.
Finegold SM. State of the art; microbiology in health and disease. Intestinal bacterial flora in autism.Anaerobe. 2011;17:367-368.
Goodwin MS, Cowen MA, Goodwin TC. Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children.J Autism Child Schizophr. 1971;1:48-62.
Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children.Appl Environ Microbiol. 2004;70:6459-6465.
Frémont M, Coomans D, Massart S, De Meirleir K. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients.Anaerobe. 2013;22:50-56.
Borody TJ, Nowak A, Finlayson S. The GI microbiome and its role in chronic fatigue syndrome: A summary of bacteriotherapy.J Australas Coll Nutr Env Med. 2012;31:3.
Borody TJ, Campbell J, Torres M, Nowak A, Leis S. Reversal of idiopathic thrombocytopenic purpura (ITP) with fecal microbiota transplantation (FMT) [abstract].Am J Gastroenterol. 2011;106:S352.
Abdollahi-Roodsaz S, Rogier R, Ederveen T, Wopereis H, Oozeer R, Koenders M, van den Berg W. Commensal intestinal microbiota drives spontaneous interleukin-1-and T helper 17-mediated arthritis in mice.Ann Rheum Dis. 2014;73:A87-A88.
Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S. The role of the microbiome in rheumatic diseases.Curr Rheumatol Rep. 2013;15:314.
Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.Elife. 2013;2:e01202.
Kyriakidis NC, Kapsogeorgou EK, Tzioufas AG. A comprehensive review of autoantibodies in primary Sjögren’s syndrome: clinical phenotypes and regulatory mechanisms.J Autoimmun. 2014;51:67-74.
Menéndez A, Gómez J, Caminal-Montero L, Díaz-López JB, Cabezas-Rodríguez I, Mozo L. Common and specific associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies in systemic lupus erythematosus.ScientificWorldJournal. 2013;2013:832789.
Szymula A, Rosenthal J, Szczerba BM, Bagavant H, Fu SM, Deshmukh US. T cell epitope mimicry between Sjögren’s syndrome Antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria.Clin Immunol. 2014;152:1-9.
Strieder TG, Wenzel BE, Prummel MF, Tijssen JG, Wiersinga WM. Increased prevalence of antibodies to enteropathogenic Yersinia enterocolitica virulence proteins in relatives of patients with autoimmune thyroid disease.Clin Exp Immunol. 2003;132:278-282.
Corapçioğlu D, Tonyukuk V, Kiyan M, Yilmaz AE, Emral R, Kamel N, Erdoğan G. Relationship between thyroid autoimmunity and Yersinia enterocolitica antibodies.Thyroid. 2002;12:613-617.
Mori K, Nakagawa Y, Ozaki H. Does the gut microbiota trigger Hashimoto’s thyroiditis?Discov Med. 2012;14:321-326.
Effraimidis G, Tijssen JG, Strieder TG, Wiersinga WM. No causal relationship between Yersinia enterocolitica infection and autoimmune thyroid disease: evidence from a prospective study.Clin Exp Immunol. 2011;165:38-43.
Sasso FC, Carbonara O, Torella R, Mezzogiorno A, Esposito V, Demagistris L, Secondulfo M, Carratu’ R, Iafusco D, Cartenì M. Ultrastructural changes in enterocytes in subjects with Hashimoto’s thyroiditis.Gut. 2004;53:1878-1880.
Reynolds LA, Finlay BB. A case for antibiotic perturbation of the microbiota leading to allergy development.Expert Rev Clin Immunol. 2013;9:1019-1030.
Strachan DP. Hay fever, hygiene, and household size.BMJ. 1989;299:1259-1260.
Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic diseases.Clin Exp Allergy. 2005;35:1511-1520.
Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL. Microbial exposure during early life has persistent effects on natural killer T cell function.Science. 2012;336:489-493.
Herbst T, Sichelstiel A, Schär C, Yadava K, Bürki K, Cahenzli J, McCoy K, Marsland BJ, Harris NL. Dysregulation of allergic airway inflammation in the absence of microbial colonization.Am J Respir Crit Care Med. 2011;184:198-205.
Stensballe LG, Simonsen J, Jensen SM, Bønnelykke K, Bisgaard H. Use of antibiotics during pregnancy increases the risk of asthma in early childhood.J Pediatr. 2013;162:832-838.e3.
Goksör E, Alm B, Pettersson R, Möllborg P, Erdes L, Aberg N, Wennergren G. Early fish introduction and neonatal antibiotics affect the risk of asthma into school age.Pediatr Allergy Immunol. 2013;24:339-344.
Jang SO, Kim HJ, Kim YJ, Kang MJ, Kwon JW, Seo JH, Kim HY, Kim BJ, Yu J, Hong SJ. Asthma Prevention by Lactobacillus Rhamnosus in a Mouse Model is Associated With CD4(+)CD25(+)Foxp3(+) T Cells.Allergy Asthma Immunol Res. 2012;4:150-156.
Schabussova I, Hufnagl K, Tang ML, Hoflehner E, Wagner A, Loupal G, Nutten S, Zuercher A, Mercenier A, Wiedermann U. Perinatal maternal administration of Lactobacillus paracasei NCC 2461 prevents allergic inflammation in a mouse model of birch pollen allergy.PLoS One. 2012;7:e40271.
Fiocchi A, Burks W, Bahna SL, Bielory L, Boyle RJ, Cocco R, Dreborg S, Goodman R, Kuitunen M, Haahtela T. Clinical Use of Probiotics in Pediatric Allergy (CUPPA): A World Allergy Organization Position Paper.World Allergy Organ J. 2012;5:148-167.
Dotterud CK, Storrø O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial.Br J Dermatol. 2010;163:616-623.
Ahn J, Sinha R, Pei Z, Dominianni C, Wu J, Shi J, Goedert JJ, Hayes RB, Yang L. Human gut microbiome and risk for colorectal cancer.J Natl Cancer Inst. 2013;105:1907-1911.
Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment.Cell Host Microbe. 2013;14:207-215.
Bonnet M, Buc E, Sauvanet P, Darcha C, Dubois D, Pereira B, Déchelotte P, Bonnet R, Pezet D, Darfeuille-Michaud A. Colonization of the human gut by E. coli and colorectal cancer risk.Clin Cancer Res. 2014;20:859-867.
Rao VP, Poutahidis T, Ge Z, Nambiar PR, Horwitz BH, Fox JG, Erdman SE. Proinflammatory CD4+ CD45RB(hi) lymphocytes promote mammary and intestinal carcinogenesis in Apc(Min/+) mice.Cancer Res. 2006;66:57-61.
Rao VP, Poutahidis T, Ge Z, Nambiar PR, Boussahmain C, Wang YY, Horwitz BH, Fox JG, Erdman SE. Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice.Cancer Res. 2006;66:7395-7400.
Rao VP, Poutahidis T, Fox JG, Erdman SE. Breast cancer: should gastrointestinal bacteria be on our radar screen?Cancer Res. 2007;67:847-850.
Fox JG, Feng Y, Theve EJ, Raczynski AR, Fiala JL, Doernte AL, Williams M, McFaline JL, Essigmann JM, Schauer DB. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens.Gut. 2010;59:88-97.
Yamamoto ML, Maier I, Dang AT, Berry D, Liu J, Ruegger PM, Yang JI, Soto PA, Presley LL, Reliene R. Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity.Cancer Res. 2013;73:4222-4232.